Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The DNA-dependent protein kinase (DNA-PK) is a DNA-end activated protein kinase that is required for efficient repair of DNA double-strand breaks (DSBs) and for normal resistance to ionizing radiation. DNA-PK is composed of a DNA-binding subunit, Ku, and a catalytic subunit, DNA-PKcs (PRKDC). We have previously shown that PRKDC is activated when the enzyme interacts with the terminal nucleotides of a DSB. These nucleotides are often damaged when DSBs are introduced by anticancer agents and could therefore prevent recognition by DNA-PK. To determine whether DNA-PK could recognize DNA strand breaks generated by agents used in the treatment of cancer, we damaged plasmid DNA with anticancer drugs and ionizing radiation. The DNA breaks were tested for the ability to activate purified DNA-PK. The data indicate that DSBs produced by bleomycin, calicheamicin and two types of ionizing radiation ((137)Cs gamma rays and N(7+) ions: high and low linear energy transfer, respectively) activate DNA-PK to levels matching the kinase activation obtained with simple restriction endonuclease-induced DSBs. In contrast, the protein-linked DSBs produced by etoposide and topoisomerase II failed to bind and activate DNA-PK. Our findings indicate that DNA-PK recognizes DSBs regardless of chemical complexity but cannot recognize the protein-linked DSBs produced by etoposide and topoisomerase II.
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PMID:Activation of the DNA-dependent protein kinase by drug-induced and radiation-induced DNA strand breaks. 1292 87

Hydroquinone (HQ) is a rodent carcinogen and a potential human carcinogen. Glutathione conjugation of HQ enhances its biological reactivity, and 2,3,5-tris-(glutathion-S-yl)hydroquinone (TGHQ) is a potent nephrotoxicant and nephrocarcinogen in the Eker rat. Moreover, a single exposure of primary epithelial cells derived from Eker rat kidneys to TGHQ transforms these cells into an immortalized phenotype (quinol-thioether transformed rat renal epithelial (QT-RRE) cells). The Eker rat bears a mutation in one allele of the tuberous sclerosis-2 (Tsc-2) tumor suppressor gene, which predisposes the animals to the development of spontaneous and chemical-induced renal cell carcinoma. Thus, the Eker rat provides a unique model for elucidating the mechanisms of renal tubular epithelial carcinogeneisis. cDNA microarray analysis of QT-RRE3 cells and of tumor tissue derived from the kidneys of Eker rats treated with TGHQ revealed alterations (by threefold or greater) in the expression of a total of 80 genes. Fifteen percent of these genes exhibited similar expression patterns in both QT-RRE cells and tumor tissue. The differentially expressed genes primarily participate in three major areas: (1) signal transduction or in the regulation of signal transduction (extracellular signal regulated kinase 2 (ERK2); protein kinase CK2; protein kinase B; c-jun; NF-kappaB; ras-related GTPases; annexins), (2) stress response, tissue remodeling, and DNA repair (glutathione-S-transferases; procollagen c proteinase enhancer; plasminogen activator; tissue inhibitor of metalloprotease 3; apurinic/apyrimidic endonuclease), and (3) electron transport and energy homeostasis (cytochrome c oxidase subunits). The changes in the expression of many of these genes was confirmed by reverse transcription (RT)-polymerase chain reactions (PCR) using primers specific for the differentially expressed genes. As an example, the annexin I and II genes, implicated in signal transduction, were highly induced in tumor tissue and also in dysplastic lesions isolated from the kidneys of rats treated chronically with TGHQ. The annexin I and II proteins were also upregulated in tumor tissue, which probably play an important role in TGHQ-induced nephrocarcinogenesis. Moreover, in the present study, a tumorigenicity assay using athymic nude mice revealed that QT-RRE cell lines formed tumors when injected in the subcutis of nude mice, providing evidence that the cells are malignantly transformed. Histopathological analysis further indicated that the tumors were composed of neoplastic cells, resembling renal carcinoma cells with varying degrees of atypia, with the presence of apoptotic and mitotic figures.
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PMID:Changes in gene expression during chemical-induced nephrocarcinogenicity in the Eker rat. 1458 99

A single double-strand break (DSB) induced by HO endonuclease triggers both repair by homologous recombination and activation of the Mec1-dependent DNA damage checkpoint in budding yeast. Here we report that DNA damage checkpoint activation by a DSB requires the cyclin-dependent kinase CDK1 (Cdc28) in budding yeast. CDK1 is also required for DSB-induced homologous recombination at any cell cycle stage. Inhibition of homologous recombination by using an analogue-sensitive CDK1 protein results in a compensatory increase in non-homologous end joining. CDK1 is required for efficient 5' to 3' resection of DSB ends and for the recruitment of both the single-stranded DNA-binding complex, RPA, and the Rad51 recombination protein. In contrast, Mre11 protein, part of the MRX complex, accumulates at unresected DSB ends. CDK1 is not required when the DNA damage checkpoint is initiated by lesions that are processed by nucleotide excision repair. Maintenance of the DSB-induced checkpoint requires continuing CDK1 activity that ensures continuing end resection. CDK1 is also important for a later step in homologous recombination, after strand invasion and before the initiation of new DNA synthesis.
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PMID:DNA end resection, homologous recombination and DNA damage checkpoint activation require CDK1. 1549 28

RNA interference (RNAi) is the process of sequence-specific post-transcriptional gene silencing triggered by double-stranded RNAs. In attempts to identify RNAi triggers that effectively function at lower concentrations, we found that synthetic RNA duplexes 25-30 nucleotides in length can be up to 100-fold more potent than corresponding conventional 21-mer small interfering RNAs (siRNAs). Some sites that are refractory to silencing by 21-mer siRNAs can be effectively targeted by 27-mer duplexes, with silencing lasting up to 10 d. Notably, the 27-mers do not induce interferon or activate protein kinase R (PKR). The enhanced potency of the longer duplexes is attributed to the fact that they are substrates of the Dicer endonuclease, directly linking the production of siRNAs to incorporation in the RNA-induced silencing complex. These results provide an alternative strategy for eliciting RNAi-mediated target cleavage using low concentrations of synthetic RNA as substrates for cellular Dicer-mediated cleavage.
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PMID:Synthetic dsRNA Dicer substrates enhance RNAi potency and efficacy. 1569 44

Distinct patterns of posttranslational histone modifications can regulate DNA-templated events such as mitosis, transcription, replication, apoptosis, and DNA damage, suggesting the presence of a "histone code" in these nuclear processes. Phosphorylation of histone H2A S129 at sites of DNA double-strand breaks (DSBs) has been implicated in damage repair in yeast. Here, we describe another phosphorylation event on serine 1 (S1) of histone H4; this event is also associated with MMS- or phleomycin-induced DSBs but not with UV-induced DNA damage. Chromatin-immunoprecipitation (ChIP) studies of an HO-endonuclease-inducible strain show that S1 phosphorylation is specifically enhanced 20- to 25-fold in nucleosomes proximal to the DSB. In addition, we show that casein kinase II (CK2) can phosphorylate H4 S1 in vitro and that null or temperature-sensitive CK2 yeast mutants are defective for induction of H4 S1 phosphorylation upon DNA damage in vivo. Furthermore, H4 S1 phosphorylation and CK2 play a role in DSB re-joining as indicated by a nonhomologous end-joining (NHEJ) plasmid assay. CK2 has been implicated in regulating a DNA-damage response; our data suggest that histone H4 S1 is one of its physiological substrates. These data suggest that this modification is a part of the DNA-repair histone code.
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PMID:Phosphorylation of histone H4 serine 1 during DNA damage requires casein kinase II in S. cerevisiae. 1582 38

Cellular responses to DNA damage involve the relocalization of checkpoint proteins to DNA double-strand breaks (DSBs). The fission yeast checkpoint mediator protein Crb2, a homolog of mammalian 53BP1, forms ionizing radiation-induced nuclear foci (IRIF). The IRIF formation by Crb2 requires histone H2A C-terminal phosphorylation and H4-K20 methylation. However, the relevance of Crb2 relocalization is uncertain, because neither histone modification is required for a checkpoint response. Here we show that these histone modifications cooperate in the same Crb2 recruitment pathway, which also requires the Tudor and BRCT motifs in Crb2. In the absence of these histone modifications, an alternative recruitment pathway is sufficient for checkpoint activation and accumulation of Crb2 at a persistent DSB generated by HO endonuclease. This parallel pathway requires a cyclin-dependent kinase phosphorylation site in Crb2 that mediates an association with another BRCT protein Cut5 (the TopBP1 homolog), which also accumulates at HO-induced DSBs. We propose that such dual recruitment mechanisms may be a common feature of DNA damage checkpoint mediators.
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PMID:Histone modification-dependent and -independent pathways for recruitment of checkpoint protein Crb2 to double-strand breaks. 1677 77

The Argonaute family member Ago1 is required for formation of pericentric heterochromatin and small interfering RNA (siRNA)-mediated post-transcriptional gene silencing in the fission yeast Schizosaccharomyces pombe. In addition, we have recently demonstrated that Ago1 function is required for enactment of cell cycle checkpoints (Carmichael, J. B., Provost, P., Ekwall, K., and Hobman, T. C. (2004) Mol. Biol. Cell 15, 1425-1435). Here, we provide evidence that the amino terminus of Ago1 binds to proteins that function in cell cycle regulation including 14-3-3 proteins. Interestingly, the amino terminus of human Ago2, the endonuclease that cleaves siRNA-targeted mRNAs, was also demonstrated to bind 14-3-3 proteins. Overexpression of the Ago1 amino terminus in yeast resulted in cell cycle delay at the G(2)/M boundary. Further investigation revealed that nuclear import of the mitosis-inducing phosphatase Cdc25 is inhibited by overexpression of the Ago1 amino terminus. Under these conditions, we found that the cyclin-dependent kinase Cdc2 is constitutively phosphorylated on tyrosine 15, thereby reducing the activity of this kinase, a situation that delays entry into mitosis. We hypothesize that 14-3-3 proteins are required for Argonaute protein functions in cell cycle and/or gene-silencing pathways.
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PMID:Interactions between the RNA interference effector protein Ago1 and 14-3-3 proteins: consequences for cell cycle progression. 1704 60

Cisplatin is an anticancer drug currently used in the treatment of genital and head and neck tumors. Its use in these and other types of tumors is narrowed by onset of chemoresistance and severe undesired side effects, like as nephro- and ototoxicity, whose mechanisms of action are only partially understood. In the present study we investigated the effects of cisplatin (cis-dichlorodiaminoplatin, CDDP) on a cell line (OC-k3) developed from organs of Corti of transgenic mice. We observed at 48 h that cell death due to cisplatin was time and concentration-dependent. The cell death displayed some morphological hallmarks of apoptosis, including nuclear fragmentation into several large nuclear fragments, surrounded by a rearranged and thickened actin cytoskeleton. No DNA laddering was detected, suggesting absence of endonuclease activity, nor annexin V positivity, suggesting absence of phosphatidylserine externalization. Several molecules protected the cells against CDDP induced cytotoxicity, including methionine, suramin and PD98059. Methionine reduced CDDP-uptake, while suramin, a polycathionic compound a specifically binding external proteins, did not. This finding suggested that suramin could exert its protective effect by acting on an intracellular transduction pathway. We tested this hypothesis by studying the effect of suramin and PD98059, a MEK inhibitor, on the mitogen activated protein kinase (MAPK) cascade. After CDDP treatment, we found an increase of phosphorylation of extracellular regulated kinases (ERK)1/2, that could be inhibited by PD98059 and suramin. These data suggest that ERK pathways can play a role in mediating the cell death induction in presence of a CDDP challenge.
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PMID:Cisplatin cytotoxicity in organ of Corti-derived immortalized cells. 1724 13

Phosphorylation of Type I restriction-modification (R-M) enzymes EcoKI, EcoAI, and EcoR124I - representatives of IA, IB, and IC families, respectively - was analysed in vivo by immunoblotting of endogenous phosphoproteins isolated from Escherichia coli strains harbouring the corresponding hsd genes, and in vitro by a phosphorylation assay using protein kinase present in subcellular fractions of E. coli. From all three R-M enzymes, the HsdR subunit of EcoKI system was the only subunit that was phosphorylated. Further, evidence is presented that HsdR is phosphorylated in vivo only when coproduced with HsdM and HsdS subunits - as part of assembled EcoKI restriction endonuclease, while the individually produced HsdR subunit is not phosphorylated. In vitro phosphorylation of the HsdR subunit of purified EcoKI endonuclease occurs on Thr, and is strictly dependent on the addition of a catalytic amount of cytoplasmic fraction isolated from E. coli. So far this is the first case of phosphorylation of a Type I R-M enzyme reported.
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PMID:Phosphorylation of Type IA restriction-modification complex enzyme EcoKI on the HsdR subunit. 1743 37

A single HO endonuclease-induced double-strand break (DSB) is sufficient to activate the DNA damage checkpoint and cause Saccharomyces cells to arrest at G(2)/M for 12-14 h, after which cells adapt to the presence of the DSB and resume cell cycle progression. The checkpoint signal leading to G(2)/M arrest was previously shown to be nuclear-limited. Cells lacking ATR-like Mec1 exhibit no DSB-induced cell cycle delay; however, cells lacking Mec1's downstream protein kinase targets, Rad53 or Chk1, still have substantial G(2)/M delay, as do cells lacking securin, Pds1. This delay is eliminated only in the triple mutant chk1Delta rad53Delta pds1Delta, suggesting that Rad53 and Chk1 control targets other than the stability of securin in enforcing checkpoint-mediated cell cycle arrest. The G(2)/M arrest in rad53Delta and chk1Delta revealed a unique cytoplasmic phenotype in which there are frequent dynein-dependent excursions of the nucleus through the bud neck, without entering anaphase. Such excursions are infrequent in wild-type arrested cells, but have been observed in cells defective in mitotic exit, including the semidominant cdc5-ad mutation. We suggest that Mec1-dependent checkpoint signaling through Rad53 and Chk1 includes the repression of nuclear movements that are normally associated with the execution of anaphase.
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PMID:The yeast DNA damage checkpoint proteins control a cytoplasmic response to DNA damage. 1758 85


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